Diphosphines

ABSTRACT

A non-symmetrical diphosphine of the formula 
     R 1 R 2 P—(Z)—PR 3 R 4   
     said diphosphine not having C 2  symmetry, wherein Z represents a chain of 2 to 4 carbon atoms which may be substituted, which chain may be saturated or unsaturated, and R 1 , R 2 , R 3  and R 4  each independently are aliphatic, aromatic or heteroaromatic groups attached to the phosphorus by carbon, nitrogen, oxygen or sulphur such that each of the moieties R 1 R 2 P and PR 3 R 4  contains a chiral centre.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional application of application Ser.No. 09/830,268 filed Oct. 9, 2001 which is a 371 of PCT/GB99/03599 filedOct. 29, 1999.

[0002] The present invention relates to diphosphines, a process fortheir preparation, metal catalysts derived from them and the use of suchcatalysts.

[0003] There has been much interest in the asymmetric hydrogenation ofalkenes in recent years using, in particular, rhodium catalysts derivedfrom P-chiral diphosphines. There is a need to improve such processes soas to enhance the enantio-selectivity.

[0004] It is commonly believed that C₂ symmetric diphosphines along withdiols and diamines are endowed with superior properties as ligands incatalysis and this is, of course, augmented by their ease of synthesis.According to the present invention, we have surprisingly found thatexcellent results can be obtained by a novel class of unsymmetricaldiphosphines.

[0005] Accordingly the present invention provides a non-symmetricaldiphosphine of the formula

R¹R²P—(Z)—PR³R⁴

[0006] wherein Z represents a chain of 2 to 4 carbon atoms which may besubstituted, which chain may be saturated or unsaturated, eg.ethylenically unsaturated, R¹, R², R³ and R⁴, which may be the same ordifferent, are aliphatic, aromatic or heteroaromatic groups attached tothe phosphorus by carbon, nitrogen, oxygen or sulphur such that eachphosphorus atom and its substituents independently form a singleenantiomer. It will be appreciated that, in general, there is a singlestereochemical configuration around each phosphorus atom. Thus one orboth phosphorus atoms may form a chiral centre. Suitable substituents ofZ are hydrogen or aliphatic, aromatic or heteroaromatic groups.

[0007] Preferably the diphosphines are 1,2-ethanes ie. the carbon chainis —(CH₂)₂—. Other typical Z groups include those having the chainstructure —C—C═C—C and —C—C═C—.

[0008] Generally, the substituents R¹, R², R³ and R⁴ will be connectedto the phosphorus atoms by carbon atoms. In a preferred embodiment, R¹and R² and/or R³ and R⁴ are linked together to form the substituted orunsubstituted 3, 4, 5, 6 or 7 membered phosphorus heterocycle andpreferably a phospholane ie. a five membered ring. This ring desirablyhas the formula

[0009] wherein R⁵ and R⁶, which may be the same or different, arehydrogen, hydroxy or C₁ to C₄ alkoxy and R⁹ and R¹⁰, which may be thesame or different, are hydrogen or C₁ to C₄ alkyl.

[0010] It is also preferred that R¹, R², R³ and/or R⁴ are substituted orunsubstituted phenyl, the substituents preferably being hydroxy or C₁,to C₄ alkoxy groups.

[0011] The alkyl and alkoxy groups are typically methyl and methoxy,respectively.

[0012] It will be appreciated that although the diphosphines arenon-symmetrical R¹, R², R³ and R⁴ may all be the same provided that thestereo orientation of R¹ and R² on the one hand, is different from thatof R³ and R⁴. The values of R¹, R², R³ and R⁴ must be such that eachphosphorus atom and its substituents independently form a singleenantiomer.

[0013] Preferred diphosphines of the present invention have the formula

[0014] wherein R⁵ and R⁶, which may be the same or different, arehydrogen, hydroxy or C₁ to C₄ alkoxy.

[0015] In accordance with another aspect of the present invention thesediphosphines can be obtained in optically pure form rather than as amixture of isomers.

[0016] It is usually convenient if at least one of the phosphorus atomsis ligated to a borane. This enhances the storage stability of thephosphine. It will be appreciated that it is a simple matter tode-boronate when it is desired to generate the ligand. Catalysts can beobtained from the diphosphine with a, generally low valent, metal suchas rhodium, iridium, ruthenium, palladium or platinum. The ligand can bereacted in known manner to generate the catalyst. For example a rhodiumcatalyst can be obtained by reaction of the ligand with (COD)₂RhBF₄. By“COD”, as used herein, is meant cyclooctadiene. The preparation of thecatalysts from the ligand can be obtained in known manner as one ofskill in the art will appreciate.

[0017] The catalysts of the present invention are generally neutral orcationic complexes. Typical counterions which can be present if they arecationic include halide, for example fluoride or chloride,tetrafluoroborate, hexafluorophosphonate, hexafluoroantimonate, orsulphonate of formula R⁷SO₃ where R⁷ is an aliphatic or aromatic group,or boronate of the formula (R⁸)₄B wherein the R⁸ groups which may be thesame or different are aromatic groups. The aromatic groups are typicallyphenyl groups which are optionally substituted. When R⁷ is aliphatic itis typically an alkyl group, for example of 1 to 4 carbon atoms such asmethyl.

[0018] The non-symmetrical diphosphines of the present invention aregenerally prepared by a Michael-type addition reaction of a nucleophilicphosphorus-containing reactant with an unsaturated, preferably anethylenically unsaturated, phosphorus-containing reactant or acyclopropyl phosphorus-containing reactant.

[0019] The nucleophilic phosphorus-containing reactant may be anycompound of the formula

R¹¹R¹²PH

[0020] wherein R¹¹ and R¹², which may be the same or different, arealiphatic, aromatic or heteroaromatic groups attached to the phosphorusby carbon, nitrogen, oxygen or sulfur. The nucleophilicphosphorus-containing reactant may also be an organometallic derivativeof the formula

R¹¹R¹²PM

[0021] which may be ionic or covalent, and in which R¹¹ and R¹² are asdefined above and M is a suitable metal.

[0022] Preferably the nucleophilic phosphorus-containing reactant is anenantiomerically pure phosphine and most preferably it is anenantiomerically pure phosphine borane such asortho-anisylphenylphosphine borane.

[0023] A phosphorus atom with electron-withdrawing substituents,attached to a double bond results in the alkene being responsive tonucleophiles. The unsaturated phosphorus-containing reactants suitablefor use in the present invention may be oxidised phosphorus-bondedalkenes, for example diethyl vinylphosphonate, which may later bereduced to provide a primary phosphine. The alkene is preferably etheneor 1,3-butadiene.

[0024] The diphosphines of the present invention are typically preparedvia a diphosphine intermediate comprising a primary phosphine andtertiary phosphine.

[0025] The primary phosphine may be elaborated by reaction with a doublyelectrophilic carbon moiety which can provide a source of chiralitygiving an enantiomerically pure product. It may be converted into aphosphorus heterocycle by reaction with a diol activated by conversionof the hydroxyl groups into leaving groups. The diol may be activatedby, for example, conversion into a halogen derivative, sulphate,sulfonate or phosphate. Diols suitable for use in the present inventioninclude C₂ to C₆ diols. The diols may be unsaturated or saturated andthey may optionally be substituted by oxygen, nitrogen, sulfur,aliphatic, aromatic or heteroaromatic groups.

[0026] It will be appreciated that other substituents may be attached tothe primary phosphine in an analogous manner.

[0027] In the process of the present invention it is advantageous toconvert one or both of the phosphorus atoms into, for example, oxide orsulfide derivatives, preferably borane derivatives, which may later beconverted back into the desired phosphine or diphosphine.

DESCRIPTION OF THE DRAWING

[0028]FIG. 1 shows an example of preparation of diphosphines accordingto the present invention.

DETAILED DESCRIPTION

[0029] An example of preparation of diphosphines according to thepresent invention is shown in Scheme 1 of FIG. 1. In Scheme 1 thediphosphines produced combine the phosphorus moieties of DIPAMP (R,R-1,2,-bis[(2-methoxyphenyl)phenylphosphino]ethane) 1 and BPE(1,2-bis[2,5-dialkyl phospholano]ethane) 2 are combined.

[0030] The synthesis shown in Scheme 1 of FIG. 1 is based on theconjugate addition of the racemic phosphineborane 3 to diethylvinylphosphonate. Alane reduction of the product 4 gives the primaryphosphineborane 5. Following deboronation, stepwise double nucleophilicdisplacement on the cyclic sulfate 6 via BuLi deprotonation gives thediphosphines 7 and 8 as a diastereomeric mixture. These compounds may beseparated by MPLC (EtOAc/pentane). The analogous compounds 10-OH and11-OH may be prepared from the mannitol derivative 9 as with acorresponding methyl ethers 10-OMe and 11-OMe.

[0031] The catalysts of the present invention may be used in theasymmetric catalytic conversion of a variety of compounds wherein a newC—B, C—Si, C—O, C—H, C—N or C—C bond is formed through the influence ofthe catalyst with control of the configuration at carbon. Such reactionsinclude, for example, catalytic hydroboration, hydrosilylation, transferhydrogenation, amination, cross-coupling, Heck olefination reactions,cyclopropanation, aziridination, allylic alkylation and cycloadditions.Preferably the catalysts are used in asymmetric hydrogenation. Preferredsubstrates for asymmetric hydrogenation include unsaturated esters suchas esters of dehydroamino acids or methylenesuccinic acids. It has beenfound that using the catalysts of the present invention, a highenantiomer excess can be obtained from unsaturated esters under mildconditions. It is believed that a single site in the ligand directsreaction by H-bonding to the reactant and improves theenantio-selectivity.

[0032] The Examples which follow further illustrate the presentinvention.

EXAMPLES

[0033] The Synthesis of Enantiomerically Pure1-(2-methoxyphenylphenylphosphino)-2-(2,5-dimethyl-3,4-dimethoxyphospholanyl)ethane.

[0034] The cyclic sulfate precursor was prepared from the knownmannitol-derived diol. (M Sanière, Y le Merrer, H El Hafa, J-C Depezay,F Rocchiccioli, J. Labelled Cpd. Radiopharm., 1991, 29. 305.) Eachcompound may be obtained on ca 5 g scales as a crystalline solid. Thecyclic sulphate 9 is preferably subjected to short-columnchromatography, to remove traces of an impurity suspected to be themonofunctionalised sulphate (itself isolated and characterised by nmr).Nonetheless, it can be purified by crystallisation from ether-pentane.No acid-induced cleavage of the isopropylidene protecting group appearsto take place.

[0035] Racemic o-anisylphenylphosphine and its corresponding boranecomplex were prepared without difficulty by the method of Imamoto. (TImamoto, T Oshiki, T Onozawa, T Katsumoto and K Sato, J. Am Chem. Soc.,112, 5244, 1990.) No scale-up problems were encountered and the reactionwas adapted to give 40 g of product without difficulty. Both PhArPH andPhArPH(BH₃) (Ar=phenyl, o-anisyl) smoothly underwent KOtBu-catalysedMichael addition to diethyl vinylphosphonate. Racemic2-anisyl-phenylphosphinoethyl diethylphosphinoethyl phosphonate 4 and2-diarylphosphinoethyl diethylphosphonate were obtained as their boranecomplexes on a 10 g scale in five minutes at room temperature. Alanereduction of this product gave the primary phosphine 5.

[0036] The cyclisation to diphosphines 10-OH and 11-OH was carried outby a two-stage sequence with butyl lithium in THF. Direct hydrolysis ofthe crude phosphine (TMSCl—MeOH) gave the diastereomeric diols which,running much more slowly on silica in pure ether than the impurities,were easily separated by column chromatography. The faster-runningdiastereomer (11-OH rf=0.25) can easily be obtained in enantiomericexcesses better than 99%.

[0037] Hydrogenation of Esters of Dehydroamino Acids orMethylenesuccinic Acid

[0038] 2 ml of degassed dichloromethane was added to (0.105 mmol) ofdiphosphine borane under argon. 1.05 mmol of HBF₄ was added then thesolution was stirred at 20-25° C. during 14 hours. Then 41 mg (0.1 mmol)of [Rh(COD)2]BF₄ was added. After being stirred for 10 minutes, thesolvent was removed in vacuo and the yellow-orange residue wastriturated three times with 5 ml of diethyl ether. The ether was removedvia cannula filtration or syringe and the orange residue dried in vacuo.These complexes were stored in Schlenk tubes under argon. For thecatalytic hydrogenation reactions the complexes were prepared justbefore use. 1 ml of a solution of Rhodium complex (2 mmol|l) in methanolwas transferred under argon via cannula or syringe to a Schlenk tubeunder argon or hydrogen containing 0.2 mmol of olefin. The solution wasplaced under hydrogen and stirred at 20-50° C. during 2-5 hours. Afterevaporation of the solvent, the product was purified by chromatographyon silica (methanol/dichloromethane). Enantiomeric excesses determinedby NMR using Eu(hfc)₃ as chiral shift reagent or by gas chromatographyusing a column Chrompack WCOT Fused Silica, CP-Chirasil-DEX CB, 25meters, inlet pressure 8 psi.

[0039] The hydrogenation of dehydroamino acids of different structuresis shown in Table 1. From this it will be seen that the configuration ofthe phosphine and of the phospholane can be “matched” or “mismatched”according to their relative configurations. For the matched cases 11-OHand 11-OMe, enantiomer excesses of up to 92% can be obtained. It willalso be seen that the extent to which the two centres influence thecourse of catalysis may differ greatly depending on the substrate. TABLE1 substrate ligand e.e.

10-OMe 11-OMe 10-OH 11-OH  7  8 19 S 85 S 43 S 92 S 60 R 38 S

10-OMe 11-OMe 10-OH 11-OH  7  8 58 S 67 S 82 S 88 S  5 R 36 R

11OMe 10-OH 11-OH 77 S 72 S 90 S*

[0040] The results of hydrogenation of itaconate esters and half-estersare shown in Table 2. The mismatched diastereomers of ligand 10 gavepoor e.e.s and are not included. For the 1-substituted monoester 15, thehydroxy-ligand 11-OH gives a superior e.e. to its methyl ether. Thereverse is true for the 4-substituted monoester 16, where the methylether 11-OMe provides the product of higher enantioselectivity. TABLE 2substrate ligand e.e.

11-OMe  8-OH 85 R 95 R

11-OMe 11-OH 93 R* 87 R

 8-OMe  8-OH 85 R 80 R*

[0041] These preliminary results indicate that, contrary to expectation,the enantioselectivity may be sensitive to a remote substituent in thephospholane ring. Inspection of molecular models suggests that the MeO-or HO-groups are axial in the 5-membered ring of the phospholane, and inthe vicinity of substituents on the coordinated alkene. Hencecooperative association between ligand and substrate may exist throughhydrogen-bonding.

1. A non-symmetrical diphosphine of the formula R¹R²P—(Z)—PR³R⁴ saiddiphosphine not having C₂ symmetry, wherein Z represents a chain of 2 to4 carbon atoms which may be substituted, which chain may be saturated orunsaturated, and R¹, R², R³ and R⁴ each independently are aliphatic,aromatic or heteroaromatic groups attached to the phosphorus by carbon,nitrogen, oxygen or sulphur such that each of the moieties R¹R²P andPR³R⁴ contains a chiral centre.
 2. A diphosphine according to claim 1,wherein Z represents a chain of 2 carbon atoms.
 3. A diphosphineaccording to claim 1, wherein R¹ and R² are linked, and/or R³ and R⁴ arelinked, to form a substituted or unsubstituted 3, 4, 5, 6 or 7 memberedphosphorus heterocycle.
 4. A diphosphine according to claim 3, whereinR¹ and R² are linked to form a ring of the formula:

wherein R⁵ and R⁶, which may be the same or different, are hydrogen,hydroxy or C₁ to C₄ alkoxy and R⁹ and R¹⁰, which may be the same ordifferent, are hydrogen or C₁ to C₄ alkyl, and all of R⁵, R⁶, R⁹ and R¹⁰cannot be hydrogen at the same time.
 5. A diphosphine according to claim1, wherein at least one of R¹, R², R³ and R⁴ is substituted orunsubstituted phenyl.
 6. A diphosphine according to claim 5, wherein thephenyl group is substituted by one or more hydroxy groups.
 7. Adiphosphine according to claim 5, wherein the phenyl group issubstituted by one or more or C₁ to C₄ alkoxy groups.
 8. A diphosphineaccording to claim 1 wherein at least one of the phosphorus atoms isligated to a borane.
 9. A catalyst comprising a diphosphine as claimedin claim 1 and a metal.
 10. A catalyst according to claim 9, wherein themetal is rhodium, iridium, ruthenium, palladium or platinum.
 11. Acatalyst according to claim 9, wherein the catalyst is neutral orcationic.
 12. A cationic catalyst according to claim 11, wherein thecounterion is halide, tetrafluoroborate, hexafluorophosphate,hexafluoroantimonate, sulfonate of the formula R⁷SO₃, wherein R⁷ is analiphatic or aromatic group, or boronate of the formula (R⁸)₄B, whereinthe groups R⁸, which may be the same or different, are aromatic groups.13. A process for preparing a diphosphine as defined in claim 1, whichprocess comprises reacting a nucleophilic phosphorus-containing reactantwith an unsaturated phosphorus containing reactant or a cyclopropylphosphorus containing reactant.
 14. A process according to claim 13,wherein the nucleophilic phosphorus-containing reactant is anenantiomerically pure phosphine.
 15. A process according to claim 14,wherein the phosphine is ligated to a borane.
 16. A process according toclaim 15, wherein the enantiomerically pure phosphine isortho-anisylphenylphosphine ligated to borane.
 17. A process accordingto claim 13, wherein the unsaturated phosphorus containing reactant isan oxidised phosphorus-bonded alkene.
 18. A process according to claim17, wherein the alkene is ethene or 1,3-butadiene.
 19. A processaccording to claim 13, wherein a diphosphine intermediate comprising aprimary phosphine and a tertiary phosphine is produced.
 20. A processaccording to claim 19, wherein the primary phosphine is converted into aphosphorus heterocycle.
 21. A process according to claim 20, wherein thephosphorus heterocycle is formed by reaction of the primary phosphinewith an enantiomerically pure diol activated by conversion of thehydroxyl groups into leaving groups.
 22. A process according to claim21, wherein the diol is activated by conversion into a halogenderivative, sulphate, sulfonate or phosphate.
 23. A process according toclaim 21, wherein the diol is mannitol.
 24. A process for the asymmetriccatalytic conversion of a compound, wherein the catalyst is one claimedin claim
 9. 25. A process according to claim 24, wherein the compound isasymmetrically hydrogenated.
 26. A process according to claim 24,wherein the compound is an unsaturated ester.